Properties of Amides


Hey it’s Professor Dave, let’s talk about amides. We’ve looked at a few different carbonyl-containing
functional groups and their derivatives, so let’s look at one more, the amide. As we recall, these consist of a carbonyl
adjacent to a nitrogen atom, with the nitrogen bonded to two other groups, either hydrogen
or alkyl in some combination. There is a lot to talk about with amides,
both in the context of their synthesis, and their role in nature, so let’s start out
by getting a more sophisticated understanding of this functional group and its properties. Let’s start out by looking at a very simple
amide, dimethyl formamide, or DMF. This has two methyls on the nitrogen atom,
and the common prefix “form” is referring to the lack of alkyl on the other side of
the carbonyl, just like with formaldehyde or formic acid. DMF is a common organic solvent, which is
polar, aprotic, and miscible with water, so we will encounter this in the lab quite frequently. One of the most interesting things about amides
is the energy barrier for rotation around the C-N bond, which is substantial. We know that sigma bonds can rotate freely,
so this may seem unexpected. But we must realize that amides have a zwitterionic
resonance structure, whereby the lone pair on the nitrogen forms a pi bond to carbon,
which kicks this pi bond up to form the oxyanion. This resonance structure is not as strongly
contributing as the other, due to the presence of formal charges, but it still contributes
to the composite, which means there is partial pi bond character between carbon and nitrogen,
and this is what limits the rotation around this bond. This is not limited to conjecture with lewis
dot structures, there is actually very strong empirical evidence for this fact in the way
of X-ray data, which invariably shows that amides are planar about this region, just
like alkenes, which is indicative of the strong double bond character. This is in stark contrast with amines, which
are pyramidal, as the lone pair occupies one of the vertices of a tetrahedron, which the
lone pair on the nitrogen in the amide does not do, because of resonance. In addition, if we look at IR spectroscopy
data, the carbonyl stretch for DMF shows up at a wavenumber of around 1675, as opposed
to a ketone, which shows up at 1700 or above. This means it takes less energy to stretch
the carbonyl in an amide than in a ketone, which is indicative of the fact that the carbonyl
in the ketone is localized, whereas in the amide it is delocalized. Chemists have calculated that the free energy
barrier of rotation around this C-N bond in DMF is around twenty kilocalories per mole,
and this is rather typical of amides. This is quite an impressive figure to have
calculated, which was actually derived from NMR data. A typical 400 megahertz proton NMR spectrum
of DMF at room temperature shows these two methyls as two distinct signals, indicating
that they are fixed in place and thus not chemically equivalent. But if you warm up the probe, slowly the two
signals broaden, and coalesce into a singlet, located exactly at the midpoint of the two
former signals. By measuring the behavior of the signals versus
temperature, and using a complex formula derived from the standard Bloch equations that we
won’t go into here, we can obtain the activation energy for the rotation around this bond that
would be required to make these methyls chemically equivalent. Now that we’ve looked at DMF for a while,
let’s try another amide. How about secondary amides, whereby the nitrogen
is bonded to one hydrogen and one alkyl group. This means the amide can exist as two isomers,
which can be assigned E and Z absolute configuration, according to the Cahn-Ingold-Prelog convention
that we already know. In practice, however, most chemists simply
refer to these as either cis or trans, to indicate the relative position of the alkyl groups. Looking at this equilibrium between the cis
and trans isomers of a secondary amide, an energy on the order of twenty kcals per mole,
which could allow for free rotation around the C-N bond, making these conformers rather
than isomers. But with cis and trans isomers of amides,
the trans is much more stable for reasons of sterics, just like we saw with alkenes,
so they will exist as 90 to 99 percent as the trans isomer, in equilibrium with small
amounts of the cis isomer. You may wonder why we are fixated on secondary amides. Well if you have made it over to my biochemistry
playlist yet, you will know that secondary amides are the basis of proteins, as when
amino acids polymerize, they will form peptide bonds, which are secondary amides. Biochemists have determined that of all the
amino acid residues in all the proteins in the body, less than 0.1 percent of them contain
cis peptide bonds, for the reasons we have just discussed. But this small amount does play a definite
role in protein structure, as well as the rate at which they rotate and fold into the
most stable conformation. One other property of amides that is relevant
to protein structure is their stability. Amides are not particularly susceptible to
hydrolysis, which is important since biomolecules are surrounded by water, and we can’t have
them falling apart all the time, or life could not exist. The half life of a typical biological amide
has been estimated as seven years, which is quite the sweet spot. As we said, if they were a little less stable,
they would fall apart too easily, but if they were a little more stable, then it would have
been too difficult for enzymes to have evolved that are able to promote hydrolysis of peptide
bonds, which would mean that metabolizing proteins would be impossible, and there would
be no way for cells to get the amino acid building blocks needed to build all the cellular
machinery. If it takes a hundred years to digest a cheeseburger,
that’s not a very good recipe for life, so we owe a lot to the very particular stability
of the amide. Later on we will spend some time talking about
protein synthesis not in the context of a cell, but from the perspective of laboratory
organic synthesis, as this is a fascinating area of study that has progressed tremendously
in the past few decades. But for now, we can just be satisfied with
an enhanced understanding of amides and their properties.

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